Plasma Profile of Immune Determinants Predicts Pathological Complete Response in Locally Advanced Breast Cancer Patients: A Pilot Study.

BACKGROUND: Complex interactions between cancer and the immune system have an impact on disease progression and therapeutic response. Our objective was to evaluate whether circulating immune-related determinants are associated with pathological complete response (pCR) in patients with locally advanced breast cancer (LABC) subjected to neoadjuvant chemotherapy (NACT). PATIENTS AND METHODS: Luminex technology was used to profile 22 cytokines, 10 chemokines, FGF2, PDGF-BB, VEGF, and Ca15-3/Ca125 glycoforms. Measurements were performed alongside standard hematological determinations on pretreatment plasma samples from 151 patients including 41 cases with pCR assessed following RECIST criteria. RESULTS: Random Forest model analysis selected platelets, eotaxin, IFN-γ, IP10, and TGFß2 as significant predictors of pCR. These immune-related features were combined into a quantitative score predictive of pCR. In patients who scored 0 or 1, none had pCR; the pCR frequency increased in relation to the score value (23.5%, 41.2%, and 78.6%, in score groups 2, 3, and 4, respectively). At multivariable logistic analysis, the pCR score was highly significant (odds ratio = 3.15 per unit increment; CI: 1.85-5.38; P < .0001); among clinical covariates (age, menopausal status, tumor stage, IHC subtype, Ki-67, CA15.3, and CA125), only Ki-67 was statistically significant (P = .013). CONCLUSION: This explorative study aimed to lay the conceptual and practical foundation that a distinctive pattern of the immune determinant blood signature at diagnosis of LABC significantly correlates with the patient's response to NACT and provides the groundwork for larger studies that could lead to a minimally invasive tool for personalized medicine.

ESMO Consensus Conference on testicular germ cell cancer: diagnosis, treatment and follow-up.

The European Society for Medical Oncology (ESMO) consensus conference on testicular cancer was held on 3-5 November 2016 in Paris, France. The conference included a multidisciplinary panel of 36 leading experts in the diagnosis and treatment of testicular cancer (34 panel members attended the conference; an additional two panel members [CB and K-PD] participated in all preparatory work and subsequent manuscript development). The aim of the conference was to develop detailed recommendations on topics relating to testicular cancer that are not covered in detail in the current ESMO Clinical Practice Guidelines (CPGs) and where the available level of evidence is insufficient. The main topics identified for discussion related to: (1) diagnostic work-up and patient assessment; (2) stage I disease; (3) stage II-III disease; (4) post-chemotherapy surgery, salvage chemotherapy, salvage and desperation surgery and special topics; and (5) survivorship and follow-up schemes. The experts addressed questions relating to one of the five topics within five working groups. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel. A consensus vote was obtained following whole-panel discussions, and the consensus recommendations were then further developed in post-meeting discussions in written form. This manuscript presents the results of the expert panel discussions, including the consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

Pazopanib in advanced germ cell tumors after chemotherapy failure: results of the open-label, single-arm, phase 2 Pazotest trial.

Background: Therapeutic options for patients with chemoresistant germ cell tumors (GCTs) are limited. Pazopanib is a selective tyrosine kinase inhibitor with distinct antiangiogenic activity. We aimed to evaluate pazopanib activity in patients with refractory GCT. Patients and methods: In the open-label, single-arm, phase 2 Pazotest study (NCT01743482), patient eligibility included failure of ≥2 platinum-based regimens, and allowed prior high-dose chemotherapy administration. Patients were given pazopanib 800 mg/day until disease progression (PD) or onset of unacceptable toxicity. Measurements of serum tumor markers (STM), computed tomography and FDG-PET were carried out at baseline, after 4 weeks of pazopanib treatment, and every 8 weeks thereafter. PD was defined as increasing levels of STM, increasing size of non-teratomatous masses, or appearance of new lesions. The study primary endpoint was progression-free survival (PFS, H0: 3-month PFS ≤ 10%, H1: ≥25%, α = 5%, ß = 20%). Results: Forty-three patients were enrolled from May 2013 to July 2016. The number of prior chemotherapy regimens was: 2 (11.6%), 3 (51.2%), >3 (37.2%). Grade 3 adverse events were observed in six patients (13.9%). Overall, 70.3% of patients had reduced levels of STM after 4 weeks. There were 2 partial responses (4.7%), 19 cases of stable disease, and 16 cases of PD (6 not evaluable by RECIST). The median follow-up duration was 29.6 months. The 3-month PFS probability was 12.8% [95% confidence interval (CI): 5.7%-28.9%]. The 24-month OS probability was 14.2% (95% CI: 6.0%-33.7%). In patients with a >50% decline in STM, the 24-month OS probability was 24.1% (95% CI: 8.3%-69.6%). The small sample size was the major limitation. Conclusions: Despite pazopanib showed potent but short-lived activity in refractory GCT, long-term survival was obtained in a proportion of treated patients. According to the kinetics of pazopanib activity, this drug may be investigated in less pre-treated patients as an optimal bridging therapy preceding and/or combined with salvage chemotherapy.

Estimates of prostate cancer burden in Italy.

Age-standardized incidence rates of prostate cancer (PC) sharply increased during the period 1990-2005 in Italian areas covered by cancer registries, while corresponding mortality rates remained nearly constant. The latest observations have reported on a reversal of the incidence trend with decreasing values after 2005. We provided incidence, mortality, and prevalence estimates at national and geographical area levels, together with time projections up to the year 2020. We applied the MIAMOD method, using as input national mortality data for the years 1970-2010 and population-based survival data for the period of diagnosis (1985-2002). We assumed relative survival of prostate cancer remained constant after the year of diagnosis (2005). The age-standardized incidence rates of PC were estimated to increase during the period 1984-2005, from 31 per 100,000 in 1984 to 93 per 100,000 in 2005. From 2005 onwards, the estimated rates declined to 71 in 2015 and to 62 in 2020. Age-standardized mortality rates slightly increased from 1970 up to about 19 per 100,000 in 1999 and then started to decrease with an estimated reduction of about 2.3% per year. Mortality projections indicated a continuing reduction, with a predicted age-standardized rate of about 12 per 100,000 in 2020. Prevalence was estimated to continuously increase up to a crude prevalence value of 1.2% in the year 2020. The results indicate that the epidemic peak of PC was reached around the year 2005 followed by declining incidence rates, while a substantial decrease in mortality, starting during the early 2000s, is expected to continue during the 2010s.

Radiotherapy or chemotherapy for clinical stage IIA and IIB seminoma: a systematic review and meta-analysis of patient outcomes.

BACKGROUND: Outcomes of radiotherapy (RT) compared with chemotherapy (CT) remain poorly defined for clinical stage (CS) IIA and IIB seminoma. We aimed to evaluate the current role of the two treatment modalities in this setting of testicular seminoma. PATIENTS AND METHODS: A systematic review and meta-analysis (MA) was carried out to identify all evaluable studies. Search was limited to studies published after 1990 and included the Medline, Embase databases, and abstracts from ASCO (GU), ESMO, AUA, and ASTRO meetings up to April 2014. Sensitivity analyses were applied including the following: CSIIA and CSIIB, paraortic + iliac RT only in both stages, RT dose (≥30 versus <30 Gy), and PEB/EP regimens only. RESULTS: Thirteen studies have been selected for MA on relapse outcome. No randomized trials compared RT and CT. There were 4 prospective and 9 retrospective studies, with a total of 607 patients receiving RT and 283 patients CT. The pooled relapse rate (RR) was similar between the RT [0.11, 95% confidence interval (CI) 0.08-0.14, P for heterogeneity = 0.096, I(2) = 38%] and CT groups (0.08, 95% CI 0.01-0.15, P for heterogeneity <0.001, I(2) = 82.5%). However, in the sensitivity analysis, the pooled RR for RT in CSIIB was 0.12 (95% CI 0.06-0.17) while it was 0.05 (95% CI 0-0.11) for CT. Long-term side-effects and incidence of second cancers were more frequently reported following RT. The overall incidence of nontesticular second malignancies was 0.04 (95% CI 0.01-0.02) in the RT group and 0.02 (95% CI 0.003-0.04) in the CT group. CONCLUSIONS: Although RT and CT appeared to be equal options in CSIIA and IIB seminoma, a trend in favor of CT for a lower incidence of side-effects and RR in CSIIB was found. This evidence is limited by the retrospective quality of studies and their small sample size.

High-dose sequential chemotherapy (HDS) versus PEB chemotherapy as first-line treatment of patients with poor prognosis germ-cell tumors: mature results of an Italian randomized phase II study.

BACKGROUND: In the late 1990s, the use of high-dose chemotherapy (HDCT) and stem-cell rescue held promise for patients with advanced and poor prognosis germ-cell tumors (GCT). We started a randomized phase II trial to assess the efficacy of sequential HDCT compared with cisplatin, etoposide, and bleomycin (PEB). PATIENTS AND METHODS: Patients were randomly assigned to receive four cycles of PEB every 3 weeks or two cycles of PEB followed by a high-dose sequence (HDS) comprising HD-cyclophosphamide (7.0 g/m(2)), 2 courses of cisplatin and HD-etoposide (2.4 g/m(2)) with stem-cell support, and a single course of HD-carboplatin [area under the curve (AUC) 27 mg/ml × min] with autologous stem-cell transplant. Postchemotherapy surgery was planned on responding residual disease in both arms. The primary end point was progression-free survival (PFS). The study was designed to detect a 30% improvement of 5-year PFS (from 40% to 70%), with 80% power and two-sided α at 5%. RESULTS: From December 1996 to March 2007, 85 patients were randomized: 43 in PEB and 42 in HDS arm. Median follow-up was 114.2 months [interquartile range (IQR): 87.7-165.8]. Complete or partial response with normal markers (PRm-) were obtained in 28 (65.1%) and 29 (69.1%) patients, respectively. Five-year PFS was 55.8% [95% confidence interval (CI) 42.8-72.8] and 54.8% (95% CI 41.6%-72.1%) in PEB and HDS arm, respectively (log-rank test P = 0.726). Five-year overall survival was 62.8% (95% CI 49.9-79.0) and 59.3% (95% CI 46.1-76.3). One toxic death (PEB arm) was recorded. CONCLUSIONS: The study failed to meet the primary end point. Furthermore, survival estimates of conventional-dose chemotherapy higher than expected should be accounted for and will likely limit further improvements in the first-line setting. CLINICALTRIALS.GOV: NCT02161692.

PF-03446962, a fully-human monoclonal antibody against transforming growth-factor ß (TGFß) receptor ALK1, in pre-treated patients with urothelial cancer: an open label, single-group, phase 2 trial.

Despite a compelling preclinical rationale for the use of anti-angiogenic drugs in urothelial cancer (UC), short-living responses have been observed in clinical trials. PF-03446962 is a novel monoclonal antibody against Activin Receptor-Like Kinase-1 (ALK1), a type I subclass of the TGFß receptor, with dose-dependent anti-angiogenic activity. An open label, single-group, phase 2 trial of PF-03446962 was conducted in salvage setting. Patients failing at least one chemotherapy regimen were eligible. Design provided PF-03446962 10 mg/Kg intravenously fortnightly until disease progression (PD) or unacceptable toxicity. Two-month progression-free survival (PFS) was the primary endpoint. The trial was registered with ClinicalTrials.gov, number NCT01620970. Fourteen patients were enrolled from October 2012 to July 2013. Median age was 64 years (interquartile range [IQR]: 58.2-69.5), 9 patients had a Bellmunt score of 1-2, median number of prior drugs was 3. One stable disease and 13 PD were recorded and the study met the futility stopping rule of interim analysis. Median PFS was 1.8 months (95 %CI, 1.4-2.0). After a median follow up of 7.4 months (IQR 4.5-10.9), 8 patients are alive. Median overall survival (OS) was 8 months (95 %CI, 2.9-not estimable). Most common toxicities were thrombocytopenia (G1-2 in 5 cases, persistent G3 in one, with 3 dose delays and 1 dose interruption), fatigue and abdominal pain (G1-2 in 4 cases each). Impairment of quality of life (ESAS score) was observed as well as an increase from baseline to +2 month median levels of vascular endothelial growth factor (VEGF) and interleukin-8. PF-03446962 had no activity as single drug in refractory UC and we do not recommend further investigation outside of the combination with agents targeting the VEGF receptor axis.

Lipochitin oligosaccharides immobilized through oximes in glycan microarrays bind LysM proteins.

Glycan microarrays have emerged as novel tools to study carbohydrate-protein interactions. Here we describe the preparation of a covalent microarray with lipochitin oligosaccharides and its use in studying proteins containing LysM domains. The glycan microarray was assembled from glycoconjugates that were synthesized by using recently developed bifunctional chemoselective aminooxy reagents without the need for transient carbohydrate protecting groups. We describe for the first time the preparation of a covalent microarray with lipochitin oligosaccharides and its use for studying proteins containing LysM domains. Lipochitin oligosaccharides (also referred to as Nod factors) were isolated from bacterial strains or chemoenzymatically synthesized. The glycan microarray also included peptidoglycan-related compounds, as well as chitin oligosaccharides of different lengths. In total, 30 ligands were treated with the aminooxy linker molecule. The identity of the glycoconjugates was verified by mass spectrometry, and they were then immobilized on the array. The presence of the glycoconjugates on the array surface was confirmed by use of lectins and human sera (IgG binding). The functionality of our array was tested with a bacterial LysM domain-containing protein, autolysin p60, which is known to act on the bacterial cell wall peptidoglycan. P60 showed specific binding to Nod factors and to chitin oligosaccharides. Increasing affinity was observed with increasing chitin oligomer length.

Analysis of plasma cytokines and angiogenic factors in patients with pretreated urothelial cancer receiving Pazopanib: the role of circulating interleukin-8 to enhance the prognostic accuracy.

BACKGROUND: Pazopanib achieved the end point of clinical activity in pretreated patients with urothelial cancer in a single-group, phase 2 trial. The objective was to identify biological predictors of clinical benefit to pazopanib in these patients. METHODS: EDTA blood samples were collected at baseline (T0) and after 4 weeks (T1) of treatment, together with radiological imaging in all 41 patients to analyse plasma circulating angiogenic factor levels by multiplex ELISA plates. Changes from T0 to T1 in marker levels were matched with response with the covariance analysis. Univariable and multivariable analyses evaluated the association with overall survival (OS), adjusted for prespecified clinical variables. Net reclassification improvement (NRI) tested the performance of the recognised Cox model. RESULTS: Increasing IL8(T1) level associated with lower response probability at covariance analysis (P=0.010). Both IL8(T0) (P=0.019) and IL8(T1) (P=0.004) associated with OS and the prognostic model, including clinical variables and IL8(T1) best-predicted OS after backward selection. The NRI for this model was 39%.When analysed as a time-varying covariate, IL8(T1) level<80 pg ml(-1) portended significantly greater response (∼80%) and 6-month OS (∼60%) probability than level ≥ 80. CONCLUSION: IL8-level changes during pazopanib allowed for a prognostic improvement and were associated with response probability.

Modified cisplatin, etoposide, and ifosfamide (PEI) salvage therapy for male germ cell tumors: long-term efficacy and safety outcomes.

BACKGROUND: Since 1985, we introduced a modified combination of etoposide, ifosfamide, and cisplatin (PEI) as second-line therapy of adult male germ cell tumors with the aim to reduce toxic effect while maintaining efficacy over the original regimen. PATIENTS AND METHODS: Patients received four cycles of ifosfamide at 2.5 g/m(2) on days 1-2, etoposide, and cisplatin at 100 and 33 mg/m(2), respectively, on days 3-5 every 21 days, followed by surgery. Results were stratified according to the International Germ Cell Consensus Classification Group-2 (IGCCCG-2). RESULTS: From February 1985 to January 2012, 189 patients were treated. 72.6% were IGCCCG-2 intermediate-to-very high risk. Thirty-five patients (18.5%) had a complete response, 67 (35.4%) a marker normalization (PRm-). Median follow-up was 122.1 months (inter-quartile range [IQR]: 71.4-232.0). Two-year progression-free and 5-year overall survival were 34.3% [95% confidence interval (CI) 28.1% to 41.9%] and 42.1% (95% CI 35.3% to 50.2%), respectively. Survival estimates compared favorably with those obtained by conventional dose chemotherapy (CDCT) regimens in each prognostic category. 70.4% of grade 3-4 neutropenia (25.5% febrile neutropenia), 48.1% thrombocytopenia, 21.2% anemia, 3.2% neurotoxic effect, and no severe renal toxic effect were recorded. CONCLUSION: Dose-modified Italian PEI should be considered as an appropriate benchmark for CDCT in the first salvage setting.

Maintaining success, reducing treatment burden, focusing on survivorship: highlights from the third European consensus conference on diagnosis and treatment of germ-cell cancer.

In November 2011, the Third European Consensus Conference on Diagnosis and Treatment of Germ-Cell Cancer (GCC) was held in Berlin, Germany. This third conference followed similar meetings in 2003 (Essen, Germany) and 2006 (Amsterdam, The Netherlands) [Schmoll H-J, Souchon R, Krege S et al. European consensus on diagnosis and treatment of germ-cell cancer: a report of the European Germ-Cell Cancer Consensus Group (EGCCCG). Ann Oncol 2004; 15: 1377-1399; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part I. Eur Urol 2008; 53: 478-496; Krege S, Beyer J, Souchon R et al. European consensus conference on diagnosis and treatment of germ-cell cancer: a report of the second meeting of the European Germ-Cell Cancer Consensus group (EGCCCG): part II. Eur Urol 2008; 53: 497-513]. A panel of 56 of 60 invited GCC experts from all across Europe discussed all aspects on diagnosis and treatment of GCC, with a particular focus on acute and late toxic effects as well as on survivorship issues. The panel consisted of oncologists, urologic surgeons, radiooncologists, pathologists and basic scientists, who are all actively involved in care of GCC patients. Panelists were chosen based on the publication activity in recent years. Before the meeting, panelists were asked to review the literature published since 2006 in 20 major areas concerning all aspects of diagnosis, treatment and follow-up of GCC patients, and to prepare an updated version of the previous recommendations to be discussed at the conference. In addition, ∼50 E-vote questions were drafted and presented at the conference to address the most controversial areas for a poll of expert opinions. Here, we present the main recommendations and controversies of this meeting. The votes of the panelists are added as online supplements.

CT-guided percutaneous cryoablation of renal masses in selected patients.

PURPOSE: We analysed our experience with computed tomography (CT)-guided percutaneous cryoablation (PCA) in patients who were not surgical candidates or refused surgery for small to medium-sized renal masses. MATERIALS AND METHODS: Two freezing cycles were applied and separated by a passive warming cycle using 1.7- and 2.4-mm cryoprobes under either general anaesthesia or sedation based on patient positioning and respiratory status. Postoperative monitoring included haematological and biochemistry evaluation and CT scan 24 h after PCA. Follow-up consisted of a multislice CT scan at 1 month and every 3 months in the first year then every 6 months thereafter. RESULTS: Thirty-seven patients (38 lesions) underwent 40 PCA procedures; 5/37 (13.5%) had a solitary kidney. Median mass size was 35 (range 12-70) mm. No complications occurred during the procedure. Clavien grade ≥2 anaemia occurred in two patients (5.4 %): one patient required 1 U of packed red blood cells; the other required an arterial embolisation. Serum creatinine did not increase in any case. Two patients showed persisting or recurrent disease at 1 and 9 months, respectively, and both could be re-treated with PCA. All other patients showed a hypodense mass 3 months after PCA, with no contrast enhancement. Subsequent examinations showed that lesion sizes decreased and CT densitometry remained stable or increased minimally, also with no contrast enhancement. CONCLUSIONS: PCA proved relatively easy and safe and could be considered an effective alternative for patients who are not surgical candidates or refuse surgery, as well as in patients with medium-sized lesions.

Burden of testicular, paratesticular and extragonadal germ cell tumours in Europe.

We provide updated estimates of survival, incidence, complete prevalence, and proportion cured for patients with testicular/paratesticular and extragonadal germ cell cancers in Europe, grouped according to the new list of cancer types developed by RARECARE. We collected data, archived in European cancer registries, with vital status information available to 31st December 2003. We analysed 26,000 cases of testicular, paratesticular and extragonadal germ cell cancers diagnosed 1995-2002, estimating that about 15,600 new testicular/paratesticular and 630 new extragonadal cancer cases occurred per year in EU27, with annual incidence rates of 31.5/1,000,000 and 1.27/1,000,000, respectively. Slightly more than 436,000 persons were alive at the beginning of 2008 with a diagnosis of testicular/paratesticular cancer, and about 17,000 with a diagnosis of extragonadal germ cell cancer. Five-year relative survival was 96% for testicular/paratesticular cancer and 71% for extragonadal germ cell cancer; the proportions cured were 95% and 69%, respectively. We found limited variation in survival between European regions except for non-seminomatous testicular cancer, for which five-year relative survival ranged from 86% in Eastern Europe to 96% in Northern Europe. Survival for all cancer types considered decreased with increasing age at diagnosis. Further investigation is required to establish the real reasons for the lower survival in Eastern Europe. Considering the high prevalence of these highly curable cancers, it is important to monitor patients long-term, so as to quantify treatment-related risks and develop treatments having limited impact on quality of life.

Targeted prostate cancer screening in men with mutations in BRCA1 and BRCA2 detects aggressive prostate cancer: preliminary analysis of the results of the IMPACT study.

OBJECTIVE: To evaluate the role of targeted prostate cancer screening in men with BRCA1 or BRCA2 mutations, an international study, IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls), was established. This is the first multicentre screening study targeted at men with a known genetic predisposition to prostate cancer. A preliminary analysis of the data is reported. PATIENTS AND METHODS: Men aged 40-69 years from families with BRCA1 or BRCA2 mutations were offered annual prostate specific antigen (PSA) testing, and those with PSA > 3 ng/mL, were offered a prostate biopsy. Controls were men age-matched (± 5 years) who were negative for the familial mutation. RESULTS: In total, 300 men were recruited (205 mutation carriers; 89 BRCA1, 116 BRCA2 and 95 controls) over 33 months. At the baseline screen (year 1), 7.0% (21/300) underwent a prostate biopsy. Prostate cancer was diagnosed in ten individuals, a prevalence of 3.3%. The positive predictive value of PSA screening in this cohort was 47·6% (10/21). One prostate cancer was diagnosed at year 2. Of the 11 prostate cancers diagnosed, nine were in mutation carriers, two in controls, and eight were clinically significant. CONCLUSIONS: The present study shows that the positive predictive value of PSA screening in BRCA mutation carriers is high and that screening detects clinically significant prostate cancer. These results support the rationale for continued screening in such men.

[Retroperitoneal surgery in the treatment of germ-cell tumors of the testis: retroperitoneal lymph node dissection (RPLND)]. / La linfoadenectomia retroperitoneale (RPLND) nel trattamento delle neoplasie germinali del testicolo.

Germ-cell tumors of the testis (GCTT) are rare, but have a high social impact. In fact they represent no more than 1% of male tumors (about 700 new cases per year in Italy), but electively occur in young patients, 20 to 40 years old, during their fully mature social and working life. More than 80% of patients are cured and return to a normal social, sexual, and working life. Improvements achieved both in diagnosis, with the use of scans (CT, MRI, US and recently PET) and of serum tumor markers alpha-fetoprotein (AFP), beta-fraction of human chorionic gonadotropin (b-HCG) and lactate dehydrogenase (LDH), and mainly in treatment, through the amelioration of radiotherapy and surgical techniques and, especially, with the introduction of Cisplatin, Etoposide and Ifosfamide in chemotherapic regimens, have made germ-cell tumor a model of "curable disease". Retroperitoneal lymph node dissection (RPLND) has indications in patients with clinical stage I (CS1) as well as in advanced disease, where it is integrated in the multimodality treatment. Anatomical studies, as well as a long-term experience, have gradually but consistently modified the surgical techniques of RPLND. Currently, "nerve sparing" RPLND represents a safe management of CS1 nonseminomatous germ cell testicular tumor with minimal morbidity and excellent outcomes. Nonetheless, surveillance and adjuvant chemotherapy are as effective as RPLND, but, in our opinion, associated with some discomforts for the patients. Laparoscopic retroperitoneal lymph node dissection (Lap-RPLND) is gaining popularity as a minimally invasive staging procedure for clinical stage I nonseminomatous testicular carcinoma, but its therapeutic role is still under investigation.

[Long-term results of laparoscopic retroperitoneal lymph node dissection (RPLND) in low-stage nonseminomatous germ-cell testicular tumors (NSGCTT) performed by a senior surgeon: 1999-2003]. / Risultati a lungo termine della linfadenectomia retroperitoneale laparoscopica nei tumori germinali non seminomatosi del testicolo; esperienza di un chirurgo anziano: 1999-2003.

BACKGROUND: Laparoscopic RPLND for low-stages NSGCTT is controversial: it is performed and recommended by excellent laparoscopic surgeons, but it is not widely used. The aim of this paper is to evaluate the results achieved by a senior surgeon, expert in open RPLND, who was introduced to laparoscopic surgery by excellent laparoscopists (LN, CU, GJ). PATIENTS AND METHODS: of the 48 operated patients, 36 had primary RPLND for clinical stage I disease (22 TIN0, 7 TxN0, 5 T2-3 N0 and 2 TIS1 N0) and 12 had post-chemotherapy surgery for IIA and IIB retroperitoneal nodes with normalized AFP and HCG. L-RPLND was performed with 4 ports and the en bloc removal of unilateral retroperitoneal nodes with the spermatic vessels. No post-operative adjuvant chemotherapy was planned for patients with documented nodal metastases as for open RPLND since 1985. RESULTS: Average operative time was 3.30' for the 36 clinical stage I patients and 4 hours for post-chemotherapy surgery. Blood loss was minimal in all cases, because of early conversion to open surgery in all patients with no immediate hemostasis at L-RPLND. Metastases were found in 6 (17%) out of the 36 clinical stage I patients: none in the 22 pTI, 1 in the 7 Tx, 3 in the 5 pT2-3 and in 2 of the 2 pT1S1 patients. Residual teratoma was found in 6 of the 12 patients who received neo-adjuvant chemotherapy for clinical stage IIA or IIB disease. The other 6 had fibrosis-necrosis. Further metastases developed in 2 of the 30 patients with negative nodes: 1 in the lung in a pT1, and 1 in a pT2 patient with increasing markers. Surprisingly, the first two pT2-3 patients with positive nodes developed liver metastases in a few months after L-RPLND. Consequently, all following patients with active metastases at L-RPLND received 2 courses of adjuvant PEB. All 4 patients who relapsed were cured, are alive and disease-free. CONCLUSIONS: L-RPLND is a very demanding operation, which appears to be more a staging procedure than a curative operation. It is ideal for pT1 clinical stage I and for post-chemotherapy stages IIA& B with residual teratoma and normalized markers, but wait & see in good risk and open RPLND in high risk patients are very competing. Only few reports compared laparoscopic versus open RPLND, but not in a randomized study.

[State of the art and controversies in the treatment of testis germ-cell tumors (TGT)].

Many different, intersecting strategies are available for managing germ-cell cancers,particularly in early-stage disease. Which is 'right' remains a matter of debate, and requires balancing efficacy against late effects, bearing in mind the complexity of treatment strategies and the available expertise.

Role of nitric oxide in the visible light-induced rapid increase of human skin microcirculation at the local and systemic levels: II. healthy volunteers.

OBJECTIVE: The aim of this study is to evaluate the skin microcirculation increase seen in healthy volunteers after a single exposure to polychromatic visible (pVIS) light, and to prove the role of nitric oxide (NO) in the development of this effect. BACKGROUND DATA: Improvement of microcirculation is one of the most important effects of laser and pVIS light therapy; however, its mechanism of action remains unknown. A main role in the regulation of vascular tone is known to be played by NO. It is produced by NO-synthase (NOS) located in membranes of many cells, including endothelial and blood cells. NOS, a biopteroflavohemoprotein, absorbs pVIS light, resulting in its activation. MATERIALS AND METHODS: The central area of the dorsal side of the right hand (24 cm2) of 42 volunteers was irradiated for 5 min with pVIS light from a Q-light (385-750 nm, 95% polarization, 40 mW/cm2, 12 J/cm2). Then for 90 min, the blood flow rate (Qas) was measured eight times, both in the area of the irradiation (local effect) and in the non-irradiated left hand (systemic effect) by using a high-frequency ultrasound Doppler device, recording Qas in human skin to a depth up to 5 mm. In the central area of the right hand of 14 volunteers an NOS inhibitor, N-monomethyl-L-arginine (L-NMMA, 0.1% solution), was iontophoretically administered prior to exposure, whereas in 10 other subjects it was administered to the left hand with subsequent exposure of the right hand. RESULTS: As soon as 2 min after exposure, Qas in the irradiated area rose on average by 32%, and in 20 min by 45%; it then decreased and in 90 min returned to the initial level. A statistically significant Qas increase in the non-irradiated hand was recorded in 5 min (+9%), and in 20 min it reached a maximum level (+39%), and 90 min later it decreased to the initial values. The presence of L-NMMA in the light-exposed area completely blocked the photoinduced rise of microcirculation, both in the irradiated and in non-irradiated hand; however, its administration to the non-irradiated hand did not prevent these effects. CONCLUSION: The increase in skin microcirculation produced by pVIS light at the local and systemic levels is due to activation of NO synthesis in the irradiated area.

[Testis tumors: what is new?].

Germ-cell tumors (GCTs) are extraordinary chemosensitive neoplasms that resemble the model for the cure of cancer even in metastatic disease. Nonetheless, a small portion of patients does not achieve a long-lasting complete response and new efforts are then required in order to further improve their healing rate. This paper summarizes what is new about the management of these tumors through dedicated sections about biology, prognosis and treatment. Special interest is then focused on the Italian reality and how it participates to the advances made by the International community.